5-fluorouracil (5-Fu) is wildly used in the treatment of a range of cancers, including esophageal carcinoma. However, response rates of 5-Fu-based chemotherapy for advanced esophageal cancer are only 25-35%. This implicates esophageal carcinoma remains a great challenge to chemotherapeutic agents. Previous studies have indicated that IGF-1 autocrine growth factor can prevent cisplatin and 5-Fu induced apoptosis in esophageal carcinoma (CE) cells. In this study, we focused on the role of Survivin, one member of the inhibitor of apoptosis (IAP) family, in the chemoresistant function of IGF-1 in CE cells.
By semiquantitative real-time PCR and immunohistochemical (IHC) analyses, we demonstrated Survivin was overexpressed in esophageal carcinoma. Survivin protein expression was also significantly correlated with poor survival of esophageal carcinoma patients. Ectopic overexpression of Survivin using replication-deficient adenovirus significantly reduced the cytotoxic effect of 5-Fu in CE cells, however, did not modify the sensitivity to cisplatin. IGF-1 treatment decreased 5-Fu-induced apoptosis with a concomitantly increased Survivin protein expression. Abolishment of Survivin expression using antisense-oligonucleotides significantly diminished IGF-1 induced protection against 5-Fu-induced apoptosis. This indicated that Survivin is an important mediator in IGF-1 induced 5-Fu chemoresistance. Finally, we found that IGF-1 up-regulated Survivin expression through both PI 3-K and CK2 signal pathways. This study explores one molecular mechanism of IGF-1 chemoresistant function and suggests that Survivin might be a valuable predictor of 5-Fu chemoresistance in esophageal carcinoma.
98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA